Malaria is an enormous, global public health problem. The pathogenesis of Plasmodium falciparum is thought to be mediated by several mechanisms, including the cytoadherence of parasite-infected red blood cells to host cells and the release of toxins from the parasites. A role for these toxins and cytoadherence in modulating host cell function is well described for antigen presenting cells and endothelium, but has not been adequately explored for syncytiotrophoblast, which is the fetal cell in direct contact with maternal blood in the placenta. This represents a critical gap in knowledge because sequestration of P. falciparum in the placenta leads to significant placental pathology and poor birth outcomes. The objective of this proposal is to characterize functional changes, particularly those relevant to immunity, in syncytiotrophoblast that are elicited by the specific binding of infected red blood cells and parasite toxins. The central hypothesis for the proposed research is that the syncytiotrophoblast responds to maternal P. falciparum infection as an innate immune cell, with capacity to impact the local maternal immune response to malaria. The rationale for the proposed research is that if syncytiotrophoblast is capable of responding immunologically to maternal malaria infection, contributing either to protection or pathogenesis, then its contribution must be considered in efforts to prevent poor birth outcomes associated with this infection. The objectives of the proposal will be achieved through one Specific Aim that will seek to characterize the influence of cytoadherent P. falciparum-infected red blood cells and other parasite components on syncytiotrophoblast immunologic function. This will be accomplished through examination of the impact of infected red blood cells, and parasite hemozoin and glycosylphosphatidyl- inositol on innate immune signaling pathways in syncytiotrophoblast as well as the ability of these cells to chemoattract mononuclear cells. Furthermore, the ability of conditioned media from the malarial-stimulated syncytiotrophoblast to influence monocyte activation and phagocytic function will be assessed. Successful completion of these studies will significantly advance our overall understanding of the immunobiology of the malarial parasite/host relationship at the maternofetal interface and will lay the groundwork for future studies designed to elucidate how this relationship can be manipulated to prevent poor birth outcomes due to maternal malarial infection. Ultimately, the knowledge gained will be pivotal in ongoing efforts to develop new diagnostics and interventions for the prevention and control of malaria during pregnancy and associated morbidity and mortality for mothers and infants living in malarious areas. PUBLIC HEALTH RELEVANCE: There are major gaps in our understanding of the pathogenesis of malaria in pregnant women, especially at the placental level. Successful completion of the proposed work will contribute to the development of improved diagnostic tools and preventive therapies for malaria that can reduce morbidity and mortality for both pregnant women and their infants who are exposed to this devastating disease.